The present invention relates to a novel 2-aryl-8-oxodihydro-purine derivative selectively acting on the peripheral-type benzo-diazepine receptors, more particularly, a 2-aryl-8-oxodihydropurine derivative having an acetamide moiety at the 7-position or the 9-position of the purine nucleus, a process for the preparation thereof, a pharmaceutical composition containing the same, and an intermediate therefor.
In the tissues of the mammals including human, there are three kinds of benzodiazepine (hereinafter, occasionally referred to as BZ) recognition sites, and each is named as central-type (xcfx891,xcfx892) benzodiazepine receptors and a peripheral-type (xcfx893) benzodiazepine receptor, respectively (hereinafter, occasionally referred to as BZxcfx891-receptor, BZxcfx892-receptor and BZxcfx893-receptor, respectively). Among them, the central-type BZ-receptors are the binding sites for BZ-compounds, and are present on the xcex3-aminobutyric acid (hereinafter, occasionally referred to as xe2x80x9cGABAxe2x80x9d)A-BZ-receptor-Clxe2x88x92 ion channel complexes. On the other hand, the peripheral-type BZ-receptor widely distributes in the central or peripheral tissues or organs such as brain, kidney, liver, heart, etc., and it especially distributes with high density in the cells of the endocrinium organs such as adrenal glands, testicles, etc., or in the cells deeply participating in the inflammation-immune system in whole body such as mast cells, lymphocytes, macrophages, blood platelets, etc., so that the physiological roles of the peripheral-type BZ-receptor have recently been drawing attention. On the other hand, the peripheral-type BZ-receptor is present a lot in the mitochondrial membrane of glial cells in the brain, and it participates in cholesterol influx into the mitochondrial membrane, and hence, it is thought to act on the biosynthesis pathway of cholesterol into neurosteroids such as progesterone, allopregnanolone, etc., via pregnenolone. Thus, it is considered that stimulation of the peripheral-type BZ-receptor accelerates the synthesis of neurosteroids in the brain which affect the chloride ion channel gating process by binding to the neurosteroid-specific recognition site (which is a different site from the benzodiazepine receptor) on the GABAA-BZ receptor-Clxe2x88x92 ion channel complexes [cf. Romeo, E., et al., J. Pharmacol. Exp. Ther., 262, 971-978 (1992)].
A compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptor has been disclosed in Japanese Patent First Publication (Kokai) No. 201756/1983 (=EP-A-94271), and since then, various compounds have been disclosed in many patent publications, etc., however, there is no compound which has actually been used as a medicament.
As a compound having a non-BZ nucleus and selectively showing an affinity for the peripheral-type BZ-receptors, the following compounds have been known.
Japanese Patent First Publication (Kokai) No. 5946/1987 (=U.S. Pat. No. 4,788,199, EP-A-205375 (patent family)) discloses that amide compounds of the following formula are bound to the peripheral-type BZ-receptor, and are useful as anxiolytics, anticonvulsants and drugs for treatment of angina pectoris, and in the treatment of immuno-deficiency syndrome. 
Japanese Patent First Publication (Kokai) No. 32058/1990 (=EP-A-346208, U.S. Pat. No. 5,026,711) discloses that 4-amino-3-carboxyquinoline compounds of the following formula show an affinity for the peripheral-type BZ-receptor both in vitro and in vivo, and can be used in the prophylaxis or treatment of human cardiovascular diseases, or as an antiallergic agent, or in the prophylaxis or treatment of infectious diseases, or in the treatment of anxiety. 
WO 96-32383 publication discloses that the acetamide derivative of the following formula selectively acts on BZxcfx893-receptor, and has anxiolytic activity and anti-rheumatoid activity so that it can be used in the treatment of anxiety-relating diseases or immune diseases. 
wherein X is xe2x80x94Oxe2x80x94 or xe2x80x94NR4xe2x80x94; R1 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkyl-lower alkyl group; R2 is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl group, etc.; R3 is a hydrogen atom, a lower alkyl group, or a hydroxy-lower alkyl group; R4 is a hydrogen atom, a lower alkyl group, etc.; R5 is a hydrogen atom, a lower alkyl group, a lower alkenyl group, a hydroxy-lower alkyl group, a substituted or unsubstituted benzyloxy-lower alkyl group, an acyloxy-lower alkyl group, a lower alkoxy-lower alkyl group, an amino group, a mono- or di-lower alkylamino group, an acylamino group, an amino-lower alkyl group, a nitro group, a carbamoyl group, a mono- or di-lower alkylcarbamoyl group, a carboxyl group, a protected carboxyl group, a carboxy-lower alkyl group, or a protected carboxy-lower alkyl group; R6 is a hydrogen atom, a lower alkyl group, a trifluoromethyl group, or a substituted or unsubstituted phenyl group, or R5 and R6 may optionally combine to form xe2x80x94(CH2)nxe2x80x94(n is 3, 4, 5 or 6); R7 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group, or a nitro group; and R8 is a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkoxy group.
The present inventors have intensively studied in order to prepare a compound acting selectively and potently on BZxcfx893-receptor, and have found the 2-aryl-8-oxodihydropurine derivatives of the following formula (I), and finally have accomplished the present invention.
An object of the present invention is to provide a novel 2-aryl-8-oxodihydropurine derivative acting selectively and potently on BZxcfx893-receptor, more particularly, to provide a 2-aryl-8-oxodihydropurine derivative having an acetamide moiety on the 7-position or the 9-position of the purine nucleus. Especially, the present invention provides a useful compound having an anti-anxiety activity. Another object of the present invention is to provide a process for preparing said compound. Still further object of the present invention is to provide a pharmaceutical composition containing said compound. Further object of the present invention is to provide an intermediate for preparing said compound. These and other objects and advantages of the present invention are obvious to any person skilled in the art from the following disclosure.
The present invention provides a 2-aryl-8-oxodihydropurine derivative of the following formula (I), a pharmaceutically acceptable acid addition salt thereof, a process for the same, and a pharmaceutical composition containing the same: 
wherein
W is a hydrogen atom, a lower alkyl group, a halogen atom, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, or a substituted or unsubstituted phenyl group;
X is a hydrogen atom, a lower alkyl group, a cycloalkyl-lower alkyl group, a substituted or unsubstituted phenyl-lower alkyl group, a lower alkenyl group, a carbamoyl group, a di-lower alkylcarbamoyl group, or a group of the formula (Q):
xe2x80x94CH(R3)CON(R1)(R2)xe2x80x83xe2x80x83(Q)
(wherein R1 is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, or a hydroxy-lower alkyl group, R2 is a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted phenyl-lower alkyl group, or a substituted or unsubstituted heteroaryl group, or R1 and R2 may combine together with the adjacent nitrogen atom to form a piperidine ring, a pyrrolidine ring, a morpholine ring, or a piperazine ring, and these rings may optionally be substituted by one or two lower alkyl groups, and R3 is a hydrogen atom, a lower alkyl group, or a hydroxy-lower alkyl group);
Y is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a lower alkenyl group, a substituted or unsubstituted phenyl-lower alkyl group, or a group of the formula (Q):
xe2x80x83xe2x80x94CH(R3)CON(R1)(R2)xe2x80x83xe2x80x83(Q)
(wherein R1, R2 and R3 are the same as defined above); and
A is a substituted or unsubstituted phenyl group, or a substituted or unsubstituted heteroaryl group;
provided that when one of X and Y of the above formula (I) is the group of the formula (Q), then the other is the same groups as defined for X or Y except for the group of the formula (Q), and also provides an intermediate of the following formula (II): 
wherein
Y2 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a lower alkenyl group, or a substituted or unsubstituted phenyl-lower alkyl group; and
A and W are the same as those as defined above.
The pharmaceutically acceptable acid addition salt of the compound of the formula (I) includes a pharmaceutically acceptable acid addition salt of the compound of the formula (I) which shows basicity enough to form an acid addition salt thereof, for example, a salt with an inorganic acid such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., or a salt with an organic acid such as maleate, fumarate, oxalate, citrate, tartrate, lactate, benzoate, methanesulfonate, etc.
The compound of the formula (I) and the intermediate thereof, i.e., the compound of the formula (II), and their acid addition acid salts may exist in the form of a hydrate and/or a solvate, and the present invention also includes these hydrates and solvates as well.
The compound of the formula (I) may have one or more asymmetric carbon atoms, and by which stereoisomers thereof are possible, and the compound of the formula (I) may exist in a mixture of two or more stereoisomers. The present invention also includes these stereoisomers, a mixture thereof, and a racemic mixture thereof.
The positions of the purine nucleus of the 2-aryl-8-oxodihydropurine derivative of the present invention are numbered as shown in the following formula, and the compounds disclosed in the present specification are named according to these numbers. 
wherein
A, W, X and Y are the same as defined above.
The terms used in the present description and claims are explained below.
The lower alkyl group and the lower alkyl moiety include a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, unless defined otherwise. The xe2x80x9clower alkyl groupxe2x80x9d is, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl, but the preferable lower alkyl group is one having 1 to 4 carbon atoms. The xe2x80x9clower alkoxy groupxe2x80x9d includes an alkoxy group having 1 to 6 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc. The xe2x80x9clower alkenyl groupxe2x80x9d includes ones having a double bond at any position except for between the 1- and 2-positions, and having 3 to 6 carbon atoms, for example, allyl, and 2-butenyl. The xe2x80x9ccycloalkyl groupxe2x80x9d includes ones having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The xe2x80x9ccycloalkyl-lower alkyl groupxe2x80x9d includes an alkyl group having 1 to 4 carbon atoms which is substituted by one of the above mentioned xe2x80x9ccycloalkyl groupsxe2x80x9d, for example, cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl. The xe2x80x9chydroxy-lower alkyl groupxe2x80x9d includes a lower alkyl group being substituted by a hydroxy group, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl. The xe2x80x9chalogen atomxe2x80x9d is fluorine, chlorine, bromine, and iodine. The xe2x80x9cmono- or di-lower alkylamino groupxe2x80x9d includes an amino group being substituted by one or two alkyl groups having 1 to 4 carbon atoms, for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, and ethylmethylamino.
The xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d includes a phenyl group which may optionally be substituted by one or two groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group and a nitro group, for example, phenyl; 2-, 3- or 4-chlorophenyl; 2-, 3- or 4-bromophenyl; 2-, 3- or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluorophenyl; 2-, 3- or 4-methylphenyl; 2-, 3- or 4-methoxyphenyl; 2-, 3- or 4-trifluoromethylphenyl; 2-, 3- or 4-hydroxyphenyl; 2-, 3- or 4-aminophenyl; 2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2-, 3- or 4-cyanophenyl; and 2-, 3- or 4-nitrophenyl.
The xe2x80x9csubstituted or unsubstituted phenyl-lower alkyl groupxe2x80x9d includes an alkyl group having 1 to 4 carbon atoms which is substituted by a phenyl group being optionally substituted by one or two groups selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group and a nitro group, for example, benzyl; 2-, 3- or 4-chlorobenzyl; 2-, 3- or 4-bromobenzyl; 2-, 3- or 4-fluorobenzyl; 2,4-dichlorobenzyl; 2,4-dibromobenzyl; 2,4-difluorobenzyl; 2-, 3- or 4-methylbenzyl; 2-, 3- or 4-methoxybenzyl; 2-, 3- or 4-trifluoromethylbenzyl; 2-, 3- or 4-hydroxybenzyl; 2-, 3- or 4-aminobenzyl; 2-, 3- or 4-methylaminobenzyl; 2-, 3- or 4-dimethylaminobenzyl; 2-, 3- or 4-cyanobenzyl; 2-, 3- or 4-nitrobenzyl; phenethyl; and 2-(4-chlorophenyl)ethyl.
The examples of a group of the formula (Axe2x80x3) as described below: 
include the above-mentioned xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d or an alkyl group having 1 to 2 carbon atoms which is substituted by the above-mentioned xe2x80x9csubstituted or unsubstituted phenyl groupxe2x80x9d, and more preferable ones are phenyl, 4- or 3-chlorophenyl, 4- or 3-bromophenyl, 4- or 3-fluorophenyl, 4-methoxyphenyl, 4-tirfluoromethylphenyl, 4-hydroxyphenyl, benzyl, 2-, 3- or 4-chlorobenzyl, 4-bromobenzyl, 3- or 4-fluorobenzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-trifluoromethylbenzyl, 4-hydroxybenzyl, phenethyl, and 2-(4-chlorophenyl)ethyl.
The xe2x80x9csubstituted or unsubstituted heteroaryl groupxe2x80x9d includes a 5-membered or 6-membered monocyclic heteroaryl group or a 5-membered or 6-membered bicyclic heteroaryl group, which may optionally be substituted by a C1-C3 alkyl group or a trifluoromethyl group, and has at least one of a nitrogen atom, an oxygen atom and a sulfur atom, for example, 2-, 3- or 4-pyridyl, 5-methyl-2-pyridyl, 2- or 3-thienyl, 2- or 3-furyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazinyl, 1-pyrazolyl, 2-imidazolyl, 2-thiazolyl, 2-isoxazolyl, 5-methyl-3-isoxazolyl, quinolyl, and isoquinolyl.
Among the compounds of the present invention, the preferable one is a compound of the formula (I) wherein A is a group of the formula (Axe2x80x2): 
(wherein R4 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group, or a nitro group, and R5 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a hydroxy group),
a pyridyl group, a thienyl group, or a furyl group, and W, X and Y are the same as defined above, or a pharmaceutically acceptable acid addition salt thereof.
The more preferable compounds are compounds of the formula (I) wherein
(a)
X is a group of the formula (Qx):
xe2x80x94CH(R31)CON(R11)(R21)xe2x80x83xe2x80x83(Qx)
wherein R11 is a lower alkyl group, and R21 is a lower alkyl group or a group of the formula (Axe2x80x3): 
(wherein R4 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group, or a nitro group, R5 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a hydroxy group, and m is 0, 1 or 2), or
R11 and R21 may combine together with the adjacent nitrogen atom to form a piperidine ring, a pyrrolidine ring, a morpholine ring, or a piperazine ring, and these rings may optionally be substituted by one or two lower alkyl groups, and R31 is a hydrogen atom, a lower alkyl group, or a hydroxy-lower alkyl group, and
Y is a hydrogen atom or a lower alkyl group, or
(b)
X is a hydrogen atom, a lower alkyl group, or a carbamoyl group, and
Y is a group of the formula (Qy):
xe2x80x94CH(R31)CON(R11)(R21)xe2x80x83xe2x80x83(Qy)
wherein R11, R21, and R31 are the same as defined above, A is the group of the above formula (Axe2x80x2), a pyridyl group, a thienyl group, or a furyl group, and W is the same as defined above, or a pharmaceutically acceptable acid addition salt thereof.
The further preferable compounds are compounds of the formula (I) wherein
(a)
X is the group of the above formula (Qx) (wherein R11 is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, R21 is an ethyl group, a propyl group, an isopropyl group, a butyl group, a phenyl group, a phenyl group being substituted by a halogen, a methoxy, a trifluoromethyl, or a hydroxy, a benzyl group, or a benzyl group being substituted by a halogen, a methoxy, a trifluoromethyl, or a hydroxy, and R31 is the same as defined above), and Y is a hydrogen atom, a methyl group, or an ethyl group, or
(b)
X is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, and Y is the group of the above formula (Qy) (wherein R11 is a methyl group, an ethyl group, a propyl group, an isopropyl group, or a butyl group, R21 is an ethyl group, a propyl group, an isopropyl group, a butyl group, a phenyl group, a phenyl group being substituted by a halogen, a methoxy, a trifluoromethyl, or a hydroxy, a benzyl group, or a benzyl group being substituted by a halogen, a methoxy, a trifluoromethyl, or a hydroxy, and R31 is the same as defined above), A is a group of the above formula (Axe2x80x2), a pyridyl group, a thienyl group, or a furyl group, and W is the same as defined above, or a pharmaceutically acceptable acid addition salt thereof.
The especially preferable compounds are 2-aryl-8-oxodihydropurine derivatives of the following formula (Ia) or (Ib), or a pharmaceutically acceptable acid addition salt thereof. 
wherein R12 and R22 are the same or different, and each an ethyl group, a propyl group or a butyl group, or R12 is a methyl group, an ethyl group, or a propyl group, R22 is a phenyl group, a halogenophenyl group, a methoxyphenyl group, a benzyl group, a halogenobenzyl group, or a methoxybenzyl group, R32 is a hydrogen atom, a methyl group, or an ethyl group, Y1 is a hydrogen atom, a methyl group, or an ethyl group, R41 is a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group, or a trifluoromethyl group. 
wherein X1 is a hydrogen atom, a methyl group, an ethyl group, or a propyl group, R12 and R22 are the same or different, and each an ethyl group, a propyl group, or a butyl group, or R12 is a methyl group, an ethyl group, or a propyl group, and R22 is a phenyl group, a halogenophenyl group, a methoxyphenyl group, a benzyl group, a halogenobenzyl group, or a methoxybenzyl group, R32 is a hydrogen atom, a methyl group, or an ethyl group, and R41 is a hydrogen atom, a halogen atom, a methyl group, a methoxy group, a nitro group, or a trifluoromethyl group.
The compounds of the formula (Ia) or (Ib) wherein R32 is a hydrogen atom are more preferable.
The examples of the most preferable compound of the present invention are the following compounds, and pharmaceutically acceptable acid addition salts thereof.
N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide;
8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide;
8,9-dihydro-2-(4-fluorophenyl)-9-methyl-N-methyl-8-oxo-N-phenyl-7H-purin-7-acetamide;
N-ethyl-8,9-dihydro-2-(4-fluorophenyl)-9-methyl-8-oxo-N-phenyl-7H-purin-7-acetamide;
7,8-dihydro-7-methyl-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide;
7-ethyl-7,8-dihydro-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide;
N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-acetamide;
N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-phenyl-9H-purin-9-acetamide;
N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-(4-chlorophenyl)-9H-purin-9-acetamide;
N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-(4-chlorophenyl)-9H-purin-9-acetamide;
The representative compounds of the present invention are, in addition to the compounds of the following Examples, the compounds of the following formulae as listed in Tables 1 and 2, and a pharmaceutically acceptable acid addition salt thereof.
In Tables 1 and 2, the following Reference Examples and Examples, the following abbreviations are used in order to simplify the disclosure.
Thus, for example, Ph-4-Cl means 4-chlorophenyl group, and Ph-4-F means 4-fluorophenyl group, and 2-Thi means 2-thienyl group.
The compounds of the present invention may be prepared, for example, by the following processes.
Process (a)
The compound of the formula (I) wherein Y is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, a lower alkenyl group, or a substituted or unsubstituted phenyl-lower alkyl group may be prepared by reacting a compound of the formula (II): 
wherein
A, W and Y2 are the same as defined above, with a compound of the formula (III):
Zxe2x80x94CH(R3)xe2x80x94CON(R1)(R2)xe2x80x83xe2x80x83(III)
wherein Z is a leaving atom or a leaving group, and R1, R2 and R3 are the same as defined above.
The leaving atom or the leaving group represented by Z in the formula (III) includes an atom or a group which may be removed in the form of HZ together with the hydrogen atom of the NH moiety of the compound (II) under the reaction conditions, for example, a halogen atom (e.g., chlorine, bromine, iodine), a lower alkylsulfonyloxy group (e.g., methanesulfonyloxy), a trihalogenomethanesulfonyloxy group (e.g., trifluoromethanesulfonyloxy), and an arylsulfonyloxy group (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy).
The reaction of the compound (II) and the compound (III) is carried out in the presence of a base under atmospheric pressure or under pressure in a suitable solvent or without a solvent. The solvent includes, for example, toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone, methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamide, and dimethylsulfoxide. The base includes, for example, sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction is usually carried out at a temperature from about xe2x88x9210xc2x0 C. to about 150xc2x0 C., preferably at a temperature from about 10xc2x0 C. to about 70xc2x0 C.
When R1 and/or R3 of the formula (III) are a hydroxy-lower alkyl group, then said hydroxy-lower alkyl group may preferably be protected by a protecting group which can be removed by hydrogenolysis. Such protecting groups include, for example, benzyloxy, 4-chlorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy. These protecting groups may easily be converted into a hydroxy group by a conventional hydrogenolysis. Beside, when R1 and/or R3 in Processes (b) to (e) as described below are a hydroxy-lower alkyl group, it is preferable to protect these groups likewise, then to remove the protecting groups to give the desired compounds.
The compound of the formula (III) may be prepared by a conventional method, for example, by the method disclosed in Japanese Patent First Publication (Kokai) 64/1987, or a modified method thereof.
The starting compound (II) is prepared, for example, by the processes as shown in the following Route A or Route B. 
wherein
R is a lower alkyl group, Z1 is a halogen atom, or an arylsulfonyloxy group or alkanesulfonyloxy group such as p-toluene-sulfonyloxy group, a methanesulfonyloxy group, or a trifluoromethanesulfonyloxy group, and A, W and Y2 are the same as defined above. 
xe2x80x83wherein A, W, Y2 and Z1 are the same as defined above.
Step 1: Halogenation or Sulfonylation
The halogenation is carried out by reacting the compound (A) or the compound (F) with a halogenating agent (e.g., phosphorus oxychloride, phosphorus tribromide). The sulfonylation is carried out, for example, by reacting the compound (A) or the compound (F) with a sulfonylating agent (e.g., methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride).
Step 2: Amination
The reaction of the compound (B) or the compound (G) with the compound (C) is carried out under atmospheric pressure or under pressure in a suitable solvent or without a solvent.
The solvent includes, for example, aromatic hydrocarbons (e.g., toluene, xylene), ketones (e.g., methyl ethyl ketone, methyl isobutyl ketone), ethers (e.g., dioxane, diglyme), alcohols (e.g., ethanol, isopropanol, butanol), acetonitrile, dimethylformamide, and dimethylsulfoxide. The reaction is preferably carried out in the presence of a base, and the base includes, for example, alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate), and tertiary amines (e.g., triethylamine), but the excess amount of the compound (C) may be used instead of a base. The reaction temperature varies according to the kinds of the starting compounds or the reaction conditions, but it is usually in the range of about 0xc2x0 C. to about 200xc2x0 C., more preferably in the range of about 20xc2x0 C. to about 100xc2x0 C.
Step 3 of Route A: Hydrolysis
The hydrolysis is carried out by a conventional method, for example, by contacting with water in a suitable solvent under acidic or basic conditions. The solvent includes, for example, alcohols (e.g., methanol, ethanol, isopropanol), dioxane, water, and a mixture of these solvents. The acid includes, for example, mineral acids (e.g., hydrochloric acid, sulfuric acid), and organic acids (e.g., formic acid, acetic acid, propionic acid, and oxalic acid). The base includes, for example, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), and alkali metal carbonates (e.g., sodium carbonate, potassium carbonate). The reaction is usually carried out at a temperature from about 20xc2x0 C. to 100xc2x0 C.
Step 3 of Route B: Reduction
The reduction is carried out by a conventional method, for example, by reacting with hydrogen in a suitable solvent in the presence of a catalyst such as palladium-carbon, Raney nickel, platinum oxide, etc. The reduction is also carried out by using a combination of a metal (e.g., tin, zinc, iron) or a metal salt (e.g., stannous chloride) and an acid (e.g., hydrochloric acid, acetic acid), or by using iron or stannous chloride alone. The solvent includes, for example, alcohols (e.g., ethanol, methanol), water, acetic acid, dioxane, tetrahydrofuran. The reaction is usually carried out at a temperature from about 0xc2x0 C. to about 80xc2x0 C., under atmospheric pressure or under pressure.
Step 4: Cyclization
The cyclization reaction is carried out in the same manner as explained in Process (b) or Process (C) as described below.
The starting compounds (A) and (F) may be commercially available ones, or can be prepared by a conventional method, for example, by the methods disclosed in J. Am. Chem. Soc., 74, 842 (1952); Chem. Ber., 95, 937 (1962); J. Org. Chem., 29, 2887 (1964); J. Med. Chem., 35, 4751 (1992); J. Org. Chem., 58, 4490 (1993); Synthesis, 86 (1985), or the methods disclosed in Reference Examples 1, 11 and 15 as described below, or a modified method thereof.
Process (b)
The compound of the formula (I) wherein X is a hydrogen atom, and Y is a group of the formula (Q) is prepared by reacting a compound of the formula (IV): 
wherein
Y3 is the group represented by the above formula (Q), and A and W are the same as defined above, with an azide compound.
The azide compound used in this process includes, for example, diphenylphosphoryl azide, sodium azide.
The reaction is carried out in the presence of a base under atmospheric pressure or under pressure in a suitable solvent or without a solvent. The solvent includes, for example, toluene, xylene, dimethoxyethane, 1,2-dichloroethane, acetone, methyl ethyl ketone, dioxane, diglyme, ethyl acetate, dimethylformamide, and dimethylsulfoxide. The base includes, for example, triethylamine, potassium carbonate, and sodium carbonate. The reaction is usually carried out at a temperature from about 10xc2x0 C. to about 150xc2x0 C., preferably at a temperature from about 30xc2x0 C. to about 120xc2x0 C.
The starting compound (IV) can be prepared by using the compound (C) in Route A that is Y3xe2x80x94NH2, and the compound (B), by the methods of Step 2 and Step 3 as shown in Route A. Moreover, the starting compound (IV) is also prepared by using the compound (B) in Route A and an amino acid, and introducing a substituted amino group on the 4-position of the pyrimidine ring by the method of Step 2 of Route A, amidating thereof by the method disclosed in Process (e) as described below, and if necessary, by alkylating the product. The detailed procedures are explained in the following Reference Example 63.
Process (c)
The compound of the formula (I) wherein X is a hydrogen atom, and Y is a group of the formula (Q) is prepared by reacting a compound of the formula (V): 
wherein
A, W and Y3 are the same as defined above, with urea, a carbonyldiimidazole or a diethyl carbonate.
The reaction is carried out in a suitable solvent or without a solvent. The solvent includes, for example, tetrahydrofuran, toluene, dimethylsulfoxide, and ethyleneglycol. The reaction is usually carried out at a temperature from about 20xc2x0 C. to about 250xc2x0 C., preferably at a temperature from about 60xc2x0 C. to about 220xc2x0 C.
The starting compound (V) is prepared by using the compound (C) in Route B that is Y3xe2x80x94NH2, and the compound (G), by the methods of Step 2 and Step 3 as shown in Route B.
Process (d)
The compound (1) wherein X is a hydrogen atom or the groups other than the group of the formula (Q), and Y is the group of the formula (Q) is prepared by reacting the compound (VI): 
wherein
A, W and Y3 are the same as defied above, which is obtained in the above Process (b), with a compound of the formula (VII):
Zxe2x80x94X2xe2x80x83xe2x80x83(VII)
wherein X2 is a hydrogen atom or the same groups for X except for the group of the formula (Q), and Z is the same as defined above.
The reaction is carried out in the same manner as in Process (a).
The starting compound (VII) may be commercially available ones, or can be prepared by a conventional method.
Process (e)
The compound (I) wherein X is a group of the formula (Q) is prepared by reacting a compound of the formula (VIII): 
wherein
A, R3, W and Y2 are the same as defined above, or a reactive derivative thereof, with a compound of the formula (IX):
HN(R13)(R23)xe2x80x83xe2x80x83(IX)
wherein R13 and R23 are each a hydrogen atom or the same groups for R1 and R2 as defined above, respectively, and when one of R13 and R23 is a hydrogen atom, then further reacting the product with a compound of the formula (X):
R24xe2x80x94Zxe2x80x83xe2x80x83(X)
xe2x80x83or the formula (XI):
R14xe2x80x94Zxe2x80x83xe2x80x83(XI)
wherein R24 is a lower alkyl group, a cycloalkyl group, or a substituted or unsubstituted phenyl-lower alkyl group, R14 is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkyl-lower alkyl group, or a hydroxy-lower alkyl group, and Z is the same as defined above, provided that when R13 is a hydrogen atom, then reacting with the compound (X), and when R23 is a hydrogen atom, then reacting with the compound (XI).
The reactive derivative of the compound (VIII) includes, for example, a lower alkyl ester (especially, methyl ester), an active ester, an acid anhydride, and an acid halide (especially, an acid chloride). The active ester includes, for example, p-nitrophenyl ester, 2,4,5-trichlorophenyl ester, and N-hydroxysuccinimide ester. The acid anhydride includes, for example, a symmetric acid anhydride and a mixed acid anhydride. The mixed acid anhydride includes, for example, a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate, and isobutyl chlorocarbonate, a mixed acid anhydride with an aralkyl chlorocarbonate such as benzyl chlorocarbonate, a mixed acid anhydride with an aryl chlorocarbonate such as phenyl chlorocarbonate, and a mixed acid anhydride with an alkanoic acid such as isovaleric acid and pivalic acid.
When the compound (VIII) per se is used, the reaction can be carried out in the presence of a condensing agent such as N,Nxe2x80x2-dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride, N,Nxe2x80x2-carbonyldiimidazole, N,Nxe2x80x2-carbonyl-disuccinimide, 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, diphenylphosphoryl azide, propanesulfonic anhydride, and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium.hexafluorophosphate.
The reaction of the compound (VIII) or a reactive derivative thereof with the compound (IX) is carried out in a solvent or without a solvent. The solvent varies according to the kinds of the starting compounds, etc., and includes, for example, aromatic hydrocarbons (e.g., benzene, toluene, xylene), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane), halogenated hydrocarbons (e.g., methylene chloride, chloroform), alcohols (e.g., ethanol, isopropanol), ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethylsulfoxide, ethylene glycol, water, etc., and these solvents may be used alone, or in the form of a mixture of two or more solvents. The reaction is carried out in the presence of a base if necessary, and the base includes, for example, alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate), and organic bases such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, but the excess amount of the compound (IX) may be used instead of a base. The reaction temperature varies according to the kinds of the starting compounds, but it is usually in the range of about xe2x88x9230xc2x0 C. to about 200xc2x0 C., preferably in the range of about xe2x88x9210xc2x0 C. to about 150xc2x0 C.
The reaction of the product obtained in the reaction between the compound (VIII) and the compound (IX), and the compound (X) or the compound (XI) is carried out by the method described in the above Process (a).
The compound (VIII) is prepared by reacting a compound of the formula (II): 
wherein
A, W and Y2 are the same as defined above, with a compound of the formula (XII):
Z1xe2x80x94CH(R3)xe2x80x94COORxe2x80x83xe2x80x83(XII)
wherein R, R3 and Z1 are the same as defined above, followed by subjecting the product to hydrolysis in a conventional manner.
The reaction is carried out in the same manner as in Process (a).
The compound (X) and the compound (XI) may be commercially available ones, or can be prepared by a conventional method.
The present compounds can also be prepared by the following methods.
The compound (I) wherein W is a lower alkoxy group is prepared by reacting a compound of the formula (I) wherein W is a halogen atom with a metal lower alkylate, and the detailed procedures thereof are explained in Example 46.
The compound (I) wherein W is a mono- or di-lower alkylamino group is prepared by reacting a compound of the formula (I) wherein W is a halogen atom with a mono- or di-lower alkylamine, and the detailed procedures thereof are explained in Example 47.
The compound (I) wherein the phenyl group is substituted by a hydroxy group is prepared by treating a compound of the formula (I) wherein the phenyl group is substituted by a methoxy group with boron tribromide or hydrogen bromide, and the detailed procedures thereof are explained in Example 174.
The desired compounds obtained in the above Processes can be isolated and purified by a conventional method such as chromatography, recrystallization, re-precipitation, etc. The compound (I) which shows basicity enough to form an acid addition salt thereof is converted into an acid addition salt thereof by treating it with various acids by a conventional method.
Various stereoisomers of the compound (I) can be separated and purified by a conventional method such as chromatography, etc.
The pharmacological activities of the present compounds are explained by the following pharmacological experiments on the representative compounds of the present invention.
Experiment 1: Central (xcfx891,xcfx892) and Peripheral (xcfx893) Benzodiazepine Receptor Binding Assays
BZxcfx891 and BZxcfx892 receptor binding assays and the preparation of receptor membrane fractions therefor were carried out according to the method of Stephens, D. N. et al. [cf., J. Pharmacol. Exp. Ther., 253, 334-343 (1990)], and BZxcfx893 receptor binding assay and the preparation of receptor membrane fraction therefor were done according to the method of Schoemaker, H. [cf, J. Pharmacol. Exp. Ther., 225, 61-69 (1983)] each with slight modification.
Receptor membrane fractions for xcfx891, xcfx892 and xcfx893 were prepared from the cerebellum (xcfx891), spinal cord (xcfx892) or kidney (xcfx893) in 7-8 week old male rats of Wistar strain, respectively, by the procedure described below.
After the cerebellum or spinal cord was homogenized with 20 volumes of ice-cold 50 mM Tris-citrate buffer (pH 7.1), the homogenate was centrifuged for 15 minutes at 40,000 g. The pellet obtained was washed 4 times by the same procedure, and frozen and stored for 24 hours at xe2x88x9260xc2x0 C. The resulting pellet, after being thawed, washed with the buffer and centrifuged, was suspended in the buffer I for the binding assay (50 mM Tris-HCl buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 1 mM MgCl2; pH 7.4) and the suspension thus obtained (containing 1 g wet tissue/40 ml) was used for the BZxcfx891 and BZxcfx892receptor binding assays. On the other hand, the kidney was homogenized with 20 volumes of the ice-cold buffer II for the binding assay (50 mM Na-K phosphate buffer containing 100 mM NaCl; pH 7.4), and the mixture was filtered through 4 sheets of gauze, and centrifuged for 20 minutes at 40,000 g. The pellet obtained was suspended in the buffer II and the suspension (containing 1 g wet tissue/100 ml) was used for the binding assay as BZxcfx893 receptor membrane source.
[3H] Flumazenil (Ro 15-1788) (final concentration: 0.3 nM for xcfx891, and 1 nM for xcfx892) and flunitrazepam (final concentration: 10 xcexcM) were used for the BZxcfx891 or BZxcfx892 receptor binding assays as the isotope-labeled and unlabeled ligands, respectively. For the BZxcfx893 receptor binding assay, [3H] 4xe2x80x2-chlorodiazepam (7-chloro-1,3-dihydro-1-methyl-5-(4-chlorophenyl)-2H-1,4-diazepin-2-one) (Ro 5-4864) (final concentration: 0.5 nM) and diazepam (final concentration: 100 xcexcM) were used as the isotope-labeled and unlabeled ligands, respectively. Incubation was performed for 30 minutes at 37xc2x0 C. in the BZxcfx891 or BZxcfx892 receptor binding assays, and for 150 minutes at 0xc2x0 C. in the BZxcfx893 receptor binding assay. The BZxcfx891 or BZxcfx892 receptor binding assays were carried out in the presence of bicuculline (final concentration: 100 xcexcM).
The binding assay was performed by the following procedure. After adding each test compound at certain known concentrations, a [3H] ligand, and the buffer I or II to each test tube, each assay was started by addition of membrane preparation (total volume of 1 ml). After incubation, the assay was terminated by filtration with suction through a Whatman GF/B glass fiber filter using a cell harvester (Brandel, USA). The filters were rapidly washed 3 times with 5 ml of ice-cold 50 mM Tris-HCl buffer (pH 7.7) for xcfx891 and xcfx892, or the buffer II for xcfx893, and transferred to scintillation vials containing 10 ml liquid scintillation cocktail (ACS-II, Amersham, USA). After being allowed to stand for a specific period, retained radioactivity was counted by a liquid scintillation spectrometer. Specific binding of [3H] ligands was calculated as the difference between amounts of radioactivity bound in the presence and absence of excess unlabeled ligands. The concentration of the test compounds causing 50% inhibition of specific binding of the [3H] ligand (IC50) was determined by probit analysis. The results are shown in Table 3. It is noted that the compounds as listed in Table 3 had affinity for the BZxcfx891 and BZxcfx892 receptors with IC50 values larger than 1000 nM.
The compounds listed in Table 3 strongly bind to the BZxcfx893 receptor, but had affinity for the BZxcfx891 and BZxcfx892 receptors with the IC50 value larger than 1000 nM. Therefore, it is apparent that the compounds of the present invention have potent and highly selective affinity for the BZxcfx893 receptor.
Experiment 2: Light and Dark Box Test (Anti-anxiety Effect)
Anti-anxiety effect of test compounds was examined in a box with light and dark compartments according to the method of Crawley, J. and Goodwin, F. K. [cf., Pharmacol. Biochem. Behav., 13, 167-170 (1980)] with slight modification.
Light and dark box test is a useful, simple and handy method for behaviorally and pharmacologically examining anti-anxiety effect of the drugs, by utilizing the habit of rodents such as mice and rats, etc. which prefer to stay in a dark place, and regarding as positive drug effect the increase of the relative stay of the animals in the light compartment which is an uncomfortable place for the animals. A number of drugs such as cholecystokinin B type receptor antagonists and benzodiazepine drugs, show positive effect in this test.
Light and dark box test was carried out using the test box device (35xc3x9717xc3x9715 cm) which comprises: a light compartment (20xc3x9717xc3x9715 cm) consisting of transparent acrylic plates and highly illuminated by an incandescent lamp (1,700 lux); a dark compartment (15xc3x9717xc3x9715 cm) being made of black acrylic plates connected to the light compartment; and at the boundary of compartments, an opening (4.4xc3x975.0 cm) in which mice can go through freely between two compartments.
Male mice of Std-ddY strain weighing 25-30 g were used in a group of 10. Each trial was started by placing a mouse in the center of the light compartment 30 minutes after oral administration of a test compound, and the time spent by the mouse in the light compartment during a 5 minute observation period was measured, and the rate of the stay of mice in the light compartment to the whole time spent in the experiment was calculated (rate of light compartment stay, %).
The anti-anxiety effect of the test compound was represented by the minimum effective dose (MED) at which the increasing rate of the relative stay in the light compartment was regarded as statistically significant (Dunnett test, significance level: 5%). The results are shown in Table. 4.
The present compounds as listed in Table 4 showed anti-anxiety effect at doses of 1 mg/kg or below, and especially the compounds of Examples 1, 2, 5, 106, 107, 136, 137, 146 and 147 showed anti-anxiety effect even at a low dose of 0.001-0.003 mg/kg.
Experiment 3: Isoniazid-induced Clonic Convulsion Test (Anti-convulsant Effect)
Isoniazid inhibits glutamate decarboxylase that catalyzes GABA biosynthesis, decrease brain GABA levels, and induces clonic convulsion. According to the method of Auta, J. et al. [cf., J. Pharmacol. Exp. Ther., 265, 649-656 (1993)] with slight modification, antagonistic effects of the test compounds on isoniazid-induced clonic convulsion were examined. Many drugs, which directly or indirectly enhance GABAA receptor function, are known to exhibit positive effect in this test. Such drugs are BZ receptor agonists represented by diazepam, neurosteroids such as allopregnanolone, allotetrahydro-deoxycorticosterone (THDOC) and BZxcfx893 receptor agonists, which enhance the synthesis of neurosteroids.
Male mice of Std-ddY strain weighing 22-24 g were used in a group of 6. Thirty minutes after oral administration of the test compounds, mice were injected with isoniazid (200 mg/kg) subcutaneously, and immediately thereafter, the mice were placed individually in plastic observation cages. The onset time of clonic convulsion was measured (cut-off time: 90 minutes). The latency in the control group was about 40 minutes.
Anti-isoniazid effect of the test compounds was expressed by the dose, which prolonged the onset time by 25% compared to that in the vehicle group (ED25). The ED25 value was calculated according to the Probit method. The results are shown in Table 5.
Experiment 4: Acute Toxicity
Male mice of Std-ddY strain weighing 25-30 g were used in a group of 10 animals for examining on the compound of Example 1. A test compound was suspended in 0.5% tragacanth and administered orally to the mice at a dose of 2000 mg/kg. Then, lethality of the mice was observed for 7 days after the treatment, and no lethality was found in mice to which the compound of Example 1 was administered.
As is shown in the results of the above pharmacological experiments, the compounds of formula (I) not only show a selective and remarkable affinity for BZxcfx893-receptor in vitro, but also show excellent pharmacological activities such as anti-anxiety effect and anti-convulsant effect, etc. in animal experiments, therefore, they are useful for prophylaxis or treatment of central nervous disorders such as anxiety-related diseases (neurosis, somatoform disorders, anxiety disorders, and others), depression, epilepsy, etc., immuno-neurologic diseases (multiple sclerosis, etc.), and circulatory organs disorders (angina pectoris, hypertension, etc.).
As the compounds showing a selective and remarkable affinity for BZxcfx893 receptor as well as showing potent anti-anxiety activity, the following compounds and pharmaceutically acceptable acid addition salts thereof are exemplified.
(1) N-ethyl-8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (the compound of Example 1)
(2) 8,9-dihydro-9-methyl-N-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (the compound of Example 2)
(3) 8,9-dihydro-2-(4-fluorophenyl)-9-methyl-N-methyl-8-oxo-N-phenyl-7H-purin-7-acetamide (the compound of Example 5)
(4) N-ethyl-8,9-dihydro-2-(4-fluorophenyl)-9-methyl-8-oxo-N-phenyl-7H-purin-7-acetamide (the compound of Example 12)
(5) 7,8-dihydro-7-methyl-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide (the compound of Example 106)
(6) 7-ethyl-7,8-dihydro-8-oxo-2-phenyl-N,N-dipropyl-9H-purin-9-acetamide (the compound of Example 107)
(7) N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-acetamide (the compound of Example 146)
(8) N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-phenyl-9H-purin-9-acetamide (the compound of Example 136)
(9) N-benzyl-N-ethyl-7,8-dihydro-7-methyl-8-oxo-2-(4-chlorophenyl)-9H-purin-9-acetamide (the compound of Example 147)
(10) N-benzyl-7,8-dihydro-N-methyl-7-methyl-8-oxo-2-(4-chlorophenyl)-9H-purin-9-acetamide (the compound of Example 137)
The compounds of the present invention can be administered either orally, parenterally or rectally. The dose of the compounds of the present invention varies according to the kinds of the compound, the administration routes, the conditions, ages of the patients, etc., but it is usually in the range of 0.01-50 mg/kg/day, preferably in the range of 0.03-5 mg/kg/day.
The compounds of the present invention are usually administered in the form of a pharmaceutical preparation, which is prepared by mixing thereof with a pharmaceutically acceptable carrier or diluent. The pharmaceutically acceptable carrier or diluent may be any conventional ones, which are usually used in the pharmaceutical field, and do not react with the compounds of the present invention. Suitable examples of the pharmaceutically acceptable carrier or diluent are, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partly pregelatinized starch, white sugar, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calcium carboxylmethylcellulose, ion exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinyl-pyrrolidone, polyvinyl alcohol, alginic acid, sodium alginate, light anhydrous silicic acid, magnesium stearate, talc, carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodium laurylsulfate, glycerin, glycerin fatty acid ester, purified lanolin, glycerogelatin, polysorbate, macrogol, vegetable oil, wax, propyleneglycol, water, ethanol, polyoxy-ethylene-hydrogenated caster oil (HCO), sodium chloride, sodium hydroxide, hydrochloric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, citric acid, glutamic acid, benzyl alcohol, methyl p-oxybenzoate, ethyl p-oxybenzoate, etc.
The pharmaceutical preparation is, for example, tablets, capsules, granules, powders, syrups, suspensions, suppositories, injection preparations, etc. These preparations may be prepared by a conventional method. In the preparation of liquids, the compound of the present invention may be dissolved or suspended in water or a suitable other solvent, when administered. Tablets and granules may be coated by a conventional method. In the injection preparations, it is preferable to dissolve the compound of the present invention in water, but if necessary, it may be dissolved by using an isotonic agent or a solubilizer, and further, a pH adjuster, a buffering agent or a preservative may be added thereto.
These preparations may contain the compound of the present invention at a ratio of at least 0.01%, preferably at a ratio of 0.1-70%. These preparations may also contain other therapeutically effective compounds as well.
The present invention is illustrated in more detail by the following Reference Examples and Examples, but should not be construed to be limited thereto.
The identification of the compounds is carried out by Elementary analysis, Mass spectrum, IR spectrum, NMR spectrum, etc.